Targeting Notch to induce anakoinosis in multiple myeloma niche

Despite therapeutic advances, multiple myeloma (MM) is still incurable due to intrinsic or acquired resistance to therapy. Twenty percent of patients are at high-risk of treatment failure as defined by tumor markers or by presentation as plasma cell leukemia; in the other cases, MM cell localization in the bone marrow (BM) milieu allows the direct interactions between MM cells and neighboring cells in the BM niche which promote survival, acquisition of drug resistance and consequent relapse. Therefore, a therapeutic strategy effective against resistant MM and able to disrupt the vicious cycle between MM cells and the BM niche and inducing anakoinosis promises to be highly effective, alone or in combination with other therapies. The Notch family includes four transmembrane receptors (Notch1-4) activated by the interaction with 5 different membrane bound ligands (Jagged1-2 and Dll1-3-4) located on the plasma membrane of adjacent cells. This results in conformational changes that enable cleavage by gamma-secretase, releasing Notch from the cell membrane and allowing its translocation to the nucleus and subsequent activation of the CSL transcription factor. In MM, Notch signaling is aberrantly activated due to an increase in the expression of Notch1-2 receptors and Jagged1-2 ligands. The concomitant aberrant expression of Notch receptors and ligands results in homotypic and heterotypic Notch activation, which affects both MM cell biology and pathological interactions with BM stroma. As a result of homotypic interactions between MM cells, the Notch pathway is hyperactivated and affects resistance to standard-of-care drugs. Concerning MM interaction with the BM milieu, our recent in vitro and ex vivo evidence indicates that Jaggedoverexpressing MM tumor cells can engage Notch receptors on BM stromal cells, activating Notch signaling and hence stimulating the secretion of inflammatory and pro-survival cytokines, i.e. IL-6, VEGF, SDF-1. This effect is accompanied by an increase in the anti-apoptotic background of MM cells due to higher levels of Bcl2 and Survivin expression that re-establish the apoptosis of MM cells following pharmacological treatment. Experiments conducted in vitro, confirmed in a zebrafish model and in primary MM cells, have demonstrated that the reported effects on MM cell biology and the pathological interaction with BM can be disrupted by knocking down Jagged1-2 in MM cells, providing a strong rationale for reestablishing apoptosis competence in MM by disrupting Notch-Jagged interactions and prompting us to study a novel Notch-directed therapeutic strategy for relapsing myeloma.